Abstract
Background and Objective: Cognitive deficits are the most challenging complications with cancer-treated patients by doxorubicin chemotherapy. An anti-vertigo drug, betahistine acts as a strong antagonist at histamine H-3 receptors and a weak agonist at histamine H-1 receptors. The present study aimed to investigate the potential of betahistine on doxorubicin-induced cognitive impairment, neuronal cholinergic deficits and neuronal inflammation in mice. Materials and Methods: To induce cognitive impairment, four doses of doxorubicin (2 mg kg(-1), i.p.) were injected once a week in groups of mice. Betahistine (5 and 10 mg kg(-1)) was administrated orally for 28 days and Elevated Plus Maze (EPM), Novel Object Recognition (NOR) and Y-Maze were used to measure cognitive behaviours. Acetylcholine (ACh) and pro-inflammatory cytokines (IL-6 and TNF-alpha) activity were estimated in brain tissues. Results: Betahistine reversed the behavioural deficits induced by doxorubicin. In EPM, it reduced the transfer latency on both acquisition and retention trails in doxorubicin-induced mice. A reversal in exploration time of both novel and familiar objects, higher exploration time with a novel object and improvement of discrimination index were observed in the betahistine administered group as compared with the doxorubicin-challenged group in the NOR test. Similarly, using the Y-Maze test, significant improvement in the number of entries in both known as well as novel arms, time spent in the novel arm and the total number of entries in the trail as well as in the test sessions by betahistine in doxorubicin-challenged mice. Mechanistically, it reversed the doxorubicin-induced cholinergic deficits in the brain by elevating the ACh levels. Additionally, betahistine attenuates the neuroinflammation by diminishing the levels of pro-inflammatory cytokines (TNF-alpha and IL-6) in the mouse brain. Conclusion: Betahistine highlights to induce neuroprotection against doxorubicin-induced cognitive impairments through facilitating cholinergic activity and ameliorating neuroinflammation in mice models.